Download Triangulation of the Monophasic Action Potential

Triangulation of the Monophasic Action Potential
Causes Flattening of the Electrocardiographic T-wave
Tanveer A Bhuiyan1, Claus Graff1, Morten B Thomsen2, Johannes J Struijk1
1
2
Aalborg University, Aalborg, Denmark
Danish National Research Foundation Centre for Cardiac Arrhythmia, University of Copenhagen,
Copenhagen, Denmark
clinical tests. We have shown that the effect of QT
prolonging drugs manifests prominently as T-wave
morphology changes when quantified by the combination
of T-wave asymmetry, flattening, and a notch score [6,7].
In the pre-clinical phase of drug development,
monophasic action potentials (MAP) are evaluated and
various changes in their shape have also been used as
signs of proarrhythmia. Prolongation of AP duration
(APD) is directly related to prolongation of the QT
interval but prolongation of the APD is not by itself
proarrhythmic provided that it is not contaminated by
other morphological changes such as triangulation [8,9].
Associations between AP shape and T-wave
morphology are to be expected, but have not been
reported yet. In [10], it was attempted to relate the
transmembrane APs from the epicardial, endocardial, and
the M-cell regions to the T-wave, but the relation between
specific morphology characteristics of the AP and the Twave was not demonstrated. Only the correlation between
the QT interval and APD was shown. Also, a transmural
ECG may not be representative of a surface ECG of the
intact in situ heart.
In the present study we have investigated the
electrophysiological effect of an Ikr blocker – sertindole on both the MAP and the T-wave at clinically relevant
doses in anesthetized dogs. Sertindole (5-Chloro-1-(4fluorophenyl)-3-(1-(2-(2-imidazolidinon-1-yl)-ethyl)-4piperidyl)-1H-indole) is an anti-psychotic compound
which was used as a medication for schizophrenia [11],
The drug was withdrawn from the market due to concerns
about possible risks of cardiac arrhythmias [12]. The
present experimental setup has been reported upon earlier
[13]; however the analysis was limited to the durations of
MAPs and QT intervals.
Here we show a significant correlation between
characteristic changes in the shape of MAPs and the
development of flat T-waves on the ECG when sertindole
is administered. We also show that the timing of the peak
changes due to drug effect is almost similar for both
MAPs and T-waves.
Abstract
It has been proposed that triangulation on the cardiac
action potential manifests as a broadened, more flat and
notched T-wave on the ECG but to what extent such
morphology
characteristics
are
indicative
of
triangulation is more unclear.
In this paper, we have analyzed the morphological
changes of the action potential under the effect of the IKr
blocker sertindole and associated these changes to
concurrent
changes
in
the
morphology
of
electrocardiographic T-waves in dogs.
We show that, under the effect of sertindole, the peak
changes in the morphology of action potentials occur at
time points similar to those observed for the peak changes
in T-wave morphology on the ECG. We further show that
the association between action potential shape and ECG
shape is dose-dependent and most prominent at the time
corresponding to phase 3 of the action potential.
1.
Introduction
Prolongation of the QT interval is a problem in drug
development because of its relation with the polymorphic
ventricular arrhythmia Torsades de Pointes (TdP) [1–3].
A large number of drugs have not been approved due to
the potential of increasing the QT interval. QT
prolongation is the traditionally used surrogate marker for
assessment of the potential risk of pro-arrhythmia, yet it
is not precise, partly because QT interval changes are
subject to measurement error [4]. In particular, druginduced T-wave changes (e.g. flattening of the T-wave)
may complicate the measurement of the QT interval.
Despite these limitations, a QTc interval of >500 ms for
an individual patient or an increase of >60 ms from
baseline are commonly regarded as thresholds for
increased risk of TdP [5].
In addition to the QT interval, which has been used as
a regulatory indicator for proarrhythmic effects, other
biomarkers, based on T-wave shape, have been used in
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Computing in Cardiology 2012; 39:757-760.
2.
Methods
2.1.
Study design
Five healthy dogs (29±4 kg) were used for the
experiment. Anaesthesia was introduced by sodium
pentobarbital (20 mg/kg intravenously) and maintained
by halothane (in O2 and N2O, 1:2). Sertindole was
administered intravenously as a 5 minute infusion to the
dogs at cumulative doses of 0.05 mg, 0.10 mg and 0.2
mg/kg, which can be considered as clinically relevant
doses. No dog had TdP at these low doses. Each dose was
followed by a thirty minute interval before next dose was
administered.
2.2.
ECG and MAP recording
A 10-lead ECG I, II, III, aVR, aVL, aVF, V1, V2, V3,
V4 was continuously recorded at a sampling frequency of
1000 samples/second. The endocardial MAP was
recorded from both the left and the right ventricle. Left
ventricular MAPs were chosen for the analysis. For each
of the dogs, 15 minutes of baseline recording was taken
just before the first dose was given.
The peak
electrophysiological effect of the drug was prominent at
each new dose after about 8-10 minutes of drug infusion.
Before the data were analysed, a moving average filter
was used to reduce the effects of noise.
Each MAP was normalized to its plateau amplitude in
order to remove any time dependent loss of MAP
amplitude due to declining contact pressure of the
catheter.
2.3.
Figure 1. Morphology changes and alignment of MAPs
and T-waves with baseline. Dotted vertical lines on the
MAP recordings indicate the 90% repolarization point
and the point of peak morphological change. The peak
morphological change is also indicated with a vertical
dotted line on the ECGs which are aligned to T-end.
Formation of representative beats
The series 10 second ECG medians for each treatment
group were aligned with the corresponding baseline
median ECG at T-end. The root mean squared difference
in T-wave shape between baseline and treatments was
calculated within the selected 130 ms window. The QT
interval and AP durations were corrected by Van de
Water’s formula [14].
From the baseline recordings, a representative baseline
median beat was constructed from both the ECG and
MAP recordings for each of the dogs. After sertindole
infusion was initiated, median beats (MAPs and ECGs)
were constructed at shorter intervals (10 second periods)
and used compared with the baseline median so the effect
of sertindole could be followed. Hence, there was one
baseline median beat for each dog and one series of
median beats for each of the three doses.
2.4.
3.
Results
Sertindole increased MAP duration and the QT
interval. Morphological changes of the MAPs and ECGs
were also observed following sertindole infusion.
Figures 2 and 3 show, for each dose, the peak
sertindole-induced changes in percentages for MAPs and
T-waves with respect to the baseline
Each of the curves in figures 3 and 4 represent the
average change from baseline for all five dogs at the time
of peak change in MAP and T-wave morphology.
Peak changes in MAP morphology with respect to the
baseline MAP were 3.4%, 4.8% and 5.5% for the three
Alignment of MAPs and ECGs
For each treatment group the series of 10 second MAP
medians were aligned with the baseline median at the
90% repolarization point as shown in figure 1. The
maximum morphological difference between the baseline
and the treatment segments were found in a window
between the 90% repolarization point and 130 ms earlier.
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of the monophasic action potential (MAP) which is a
regular effect of an Ikr blocker. This effect can be
referred as triangulation because the action potential
assumes a more triangular appearance when this phase of
repolarization slows down. Sertindole also affected the
morphology of electrocardiographic T-waves. The
morphological changes in this case can be described as
flattening of the T-wave. Both MAP changes and ECG
changes were dependent on the dose administered and
importantly, the peak changes for both the MAP and ECG
occurred at almost the same point in time. These timealigned changes indicate that the pronounced changes in
T-wave morphology were mostly caused by shape
changes in phase 3 of the cardiac action potential.
Whether this correlation exist for all IKr inhibiting drugs
or only those drugs which cause triangulation of the
cardiac action potential and potentially cause
proarrhythmia is presently uncertain. Invasive studies
measuring Triangulation, Reverse use dependency,
electrical Instability and Dispersion (TRIaD) have
suggested that TRIaD may have a better predictive value
for the occurrence of TdP, than the action potential
prolongation (QT prolongation) [8, 9]. The potential
value of TRIaD was largely substantiated in more than
700 trial drugs [15].
We have shown that a torsadogenic drug which causes
triangulation of the action potential also has a large effect
on the electrocardiographic T-wave. We believe that
computerized measures of T-wave morphology have the
potential to be an important addition to QT interval
measurements because such measures may contribute to
an expanded ECG safety evaluation in future drug studies
through more careful characterization of repolarization
abnormalities. We therefore propose to further investigate
how TRIaD representations on the cardiac action
potential are reflected in the ECG
cumulative doses and they occurred at 14 ms, 21 ms and
23 ms before the 90% repolarization point, respectively.
The peak changes in T-wave morphology with respect to
the baseline were 47%, 63% and 73% and they occurred
at 29 ms, 30 ms and 40 ms before the end of the T-wave.
Figure 2. Peak sertindole-induced changes in MAP
morphology for each of the three doses. Each curve is the
average of all 5 dogs. MAP shape changes are dosedependent and most prominent in phase 3 of the action
potential.
5.
Triangulation of the monophasic action potential
following administration of a torsadogenic drug was
associated with a flattening of the electrocardiographic Twave. Further studies are needed to investigate the
relationship between triangulation on the action potential
and
changes
in
the
morphology
of
the
electrocardiographic T-wave.
Figure 3. Peak sertindole-induced changes in T-wave
morphology. Each curve is the average of all 5 dogs.
ECG shape changes are dose-dependent and most
prominent at the time corresponding to phase 3 of the
action potential.
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4.
Conclusion
Discussion
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Address for correspondence:
Tanveer Ahmed Bhuiyan
Department of Health Science and Technology
Aalborg University
Fredrik Bajers Vej 7 C1-217
9220 Aalborg, Denmark
E-mail address: [email protected]
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